The normal cellular counterpart and etiology of B cell chronic lymphocytic leukemia (CLL), the most common leukemia in Western counties, still remains unknown. Fundamental to this knowledge gap is a limited awareness of the biological heterogeneity of human memory B cells. These issues are important challenges for determining CLL pathogenesis because without a more thorough understanding of this relationship, improving prevention, diagnostic, treatment, and vaccination strategies will continue to be difficult. The long-term goal is to understand the link between normal B cell development and the pathogenesis of CLL. The objective of this proposal is to analyze the molecular and functional features of newfound subpopulations in the human memory B cell repertoire to define the normal CLL-counterpart. The central hypothesis is that members of an extended family of Fc receptor-like (FCRL) molecules with immunoregulatory function mark subsets of memory B cells from which CLL derives. The rationale for the proposed research is that the discovery of the B cell subpopulation from which CLL arises will provide new appreciation of its pathogenesis and enable more informed approaches for treating this incurable lymphoproliferative disorder. Based on our preliminary data, this hypothesis will be tested in two specific aims: Aim 1 proposes to determine whether a memory B cell subset defined by FCRL expression molecularly resembles the pre-transformed CLL counterpart and Aim 2 will investigate the functional characteristics of FCRL expressing memory B cells. The contribution of this research will be significant because it will provide a comprehensive analysis of newfound memory B cell subpopulations to reveal for the first time the cellular origin(s) of CLL, help elucidate unexplored mechanisms involved in humoral immunity, and generate new knowledge for developing preventive and interventional strategies that link immune dysregulation and cancer. The proposed research is innovative because it overcomes previous less selective approaches by employing unique biomarkers of CLL possessing modulatory function that define previously unappreciated subsets in the human memory B cell repertoire resembling CLL cells. This novel strategy, will disclose molecular and functional features of these cells, shift our recognition of memory B cell diversity, assist in unearthing the CLL counterpart, and advance understanding of its pathogenesis. These outcomes are expected to have a positive impact because they will provide new avenues for researchers to develop preventative and therapeutic strategies for the treatment of CLL and other B cell disorders. Importantly, these studies should advance fundamental understanding of the dynamic interface between humoral immunity and the malignant transformation of B cells.